Photodynamic therapy (PDT) is a medical treatment that employs a combination of light and a photosensitizing agent to generate a cytotoxic effect of cancerous or other unwanted tissues. It possesses high effectiveness and safety compared with the conventional chemotherapy. The widely accepted PDT mechanism is that upon irradiation, the photosensitizer successively generates active oxygen species of high reactivity that the target molecules. Contrast with the traditional chemical medicine which can only kill one target molecule at a time, the PDT possesses remarkable high-effectiveness. On the other hand, the PDT has dual selectivity including drug-orientation and light-orientation, which avoids or decreases the damage to normal tissues, and increases the drug safety. This is important for cancer and AIDS treatments.
Photodynamic therapy (PDT) consists of introducing a photoactive drug into the body and subsequent illumination of tumor tissue by visible or near infrared light. In the presence of oxygen, illumination activates the drug and in turn produces reactive oxygen species leading to tissue damage. Owing to its advantages such as its relative selectivity in most sites, its compatibility with other treatment, its repeatability, its ease of delivery etc., PDT is slowly finding its place as a useful cancer treatment for certain types of cancers or clinical situation, such as early stage cancers of the lung, esophagus, stomach, cervix and cervical dysplasia, etc. [1].
With the rapid development of laser and optical-fiber techniques, the issue of light source in PDT is being resolved. The selection of the photosensitizer in PDT treatment becomes more critical. At present, the most popular photodynamic agent, photofrin, shows distinct curative effect on treating inchoate cancer, such as vesical, pulmonary and gastric cancers etc. Lipson et. al. employed hematoporphrin derivatives (HPD) to detect and control the cancer growing, and to treat galactophore cancer for the first time in 1966. Kelly and Snell reported that HPD had obviously photodynamic curative effect on the vesical cancer in Journal of Urology (1976, 115, 150). Dougherty et. al. reported that they used HPD as photosensitizer to study their photodynamic activities against thousands of cases of cerebric, jugular and ocular cancers etc. in Journal of NATO Cancer Institute (1975, 55, 115), and obvious curative effects are obtained. In 1978, Dougherty used HPD as photosensitizer to treat malignant cutaneous cancer and subcutaneous tumor, indicating that 111 pathological changes are cured completely or partially among 113 pathological changes. Porphyrin sensitizer is a π-conjugated system composed by four pyrrole rings and four methylene bridges, HPD and dihematoporphyrin ether or ester (DHE) is the comprehensive agent used in clinical therapy. When HPD is up to certain concentration, aggregation occurred readily in vitro and in vivo, which decreased the photodynamic activities of HPD. In Cell Biochemistry Function (1985, 3, 15), El-Far et al. reported the HPD are lipophilic and exhibited a certain extent of cancer cells-localization ability. They can be enriched selectively in cancer tissues, and the localization action and photosensitized activities are dependent on their hydrophobicility, aggregation and charge distributing.
To date, only Photofrin® has been approved by health boards in Canada, Japan, the Netherlands and the United States [2]. In spite of the favorable results obtained with Photofrin, some important factors still limit the efficacy of PDT, including its complex composition, the low extinction coefficient in the red spectral region and the prolonged cutaneous phototoxicity (3]. This is undoubtedly encouraging the search for more ideally suited photosensitizers.
Although the PDT using HPD as photosensitizers had received great attention, there are still some serious disadvantageous, i.e. complicated components, little absorption in the photodynamic window (600–900 nm), slow metabolism, toxicity and side-effect.
To overcome these limitations, all kinds of new photosensitizers are explored in recent years. The naturally occurring polycyclic quinones, hypocrellins, isolated from the fungus hypocrella bambuase (B. Et Br) sacc, grew abundantly in the southwestern part of China. Their high content (3–4%) in the fungus and easy separation and purification had received most attentions in the passed 20 years.
Hypocrellins derive their name from Hypocrella bambusae sacc., a parasitic fungus of the Sinarundinaria species, which grows abundantly in the northwestern region of the Yunnan Province (People's Republic of China), the southeastern region of Tibet, and certain parts of Sri Lanka. Hypocrellins belong to the general class of perylenequinoid (PQP) pigments, and include hypocrellin A (HA) and hypocrellin B (HB).
In China some hospitals had used hypocrellins as photodynamic agent to treat certain dermatosis, such as pudendum bleaching, vitiligo and psoriasis. In 1980, Xiang-yi Wan and Zi-hua Luo reported that hypocrellin could be used to treat pudendum bleaching and cutaneous blotch in Kexue Tongbao (1980, 25, 1148) (in Chinese) and Yunnan Yiyao (1980, 1, 20) (in Chinese), respectively. Hypocrellin is used gradually to treat lichenification, vitiligo, and psoriasis and scald head. Yuan-teng Chen et al. identified one of the effective components, hypocrellin A (HA), in Liebigs Ann. Chem. (1981, 1880). Manhua Zhang and Li Liang et al. identified the other effective component of hypocrellin, hypocrellin B (HB) in Kexue Tongbao (1988, 33, 518) (in Chinese). Manhua Zhang et al. have studied the structures, photochemistry, photophysics, photobiology and cytology of hypocrellins for more than ten years. We observed that hypocrellins consisted of HA {3,10-dihydroxyl-4,9-dione-1,12-(2′-hydroxyl-2′-methyl-3′-actyl)propilidene(1′,3′)-2,6,7,11-tetramethoxyl-perylene} (see structure I) and HB {3,10-dihydroxyl-4,9-dione-1,12-(2′-methyl-3′-actyl-2′,3′-dehydro)propilidene(1′,3′)-2,6,7,11-tetramethoxyl-perylene} (see structure II).

As a new kind of photosensitizers, they possess several advantages, including easy preparation and purification, low toxicity, high stability, no aggregation, rapid metabolism, low side effect and selective localization in cancer tissues. These properties make them as promising second-generation photosensitizers. Lown et. al. reported that HB possessed distinct anti-AIDS action in Photochemistry and Photobiology (1997, 65, 352). However their little absorption in the photodynamic window limits their application in PDT. Hypocrellins, owing to their pure composition, favorable red light, absorption spectra, high quantum yields of singlet oxygen and facility for side-directed chemical modification, have been selected as potential photosensitizers for PDT [4]. A lot of derivatives of the parent hypocrellin B (HB) have been synthesized and studied. Some of them have shown promising anticancer properties (5–11). To overcome these limitations, lots of structural modifications of hypocrellins have been made. In 1994–1995, we and Lown prepared amino-substituted hypocrellins at about the same time. The amino-substituted hypocrellins exhibited strong absorption in the photodynamic window. With the aid of laser, they showed much higher photodynamic activities than their parent hypocrellins. Lown reported the photodamage to cancer cells by amino-substituted hypocrellins in detail in Photochemistry and Photobiology (1997, 65, 714). The original peri-hydroxylated perylenequinone structure of hypocrellins is altered in the amino-substituted derivatives prepared by Dr. Lown (see structures III and IV, the parent compounds of III and IV are isomers), which changed the photoactive position of hypocrellins. The method of amino-substituted HB reported by Lown is undesirable due to the numerous steps.

Manhua Zhang et al. reported that the mercapto-substituted hypocrellins exhibit little absorption in the photodynamic window due to the undesirable photoactive position.